Cirrhosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Overview

Cirrhosis occurs due to long term liver injury which causes an imbalance between matrix production and degradation. Early disruption of the normal hepatic matrix results in its replacement by scar tissue, which in turn has deleterious effects on cell function.

Pathophysiology

  • The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma, blocking the portal flow of blood through the organ and disturbing normal function.
  • The development of fibrosis requires several months, or even years, of ongoing injury.
  • The fibrous tissue bands (septa) separate hepatocyte nodules, which eventually replace the entire liver architecture, leading to decreased blood flow throughout.
  • The spleen becomes congested, which leads to hypersplenism and increased sequestration of platelets.
  • Portal hypertension is responsible for the most severe complications of cirrhosis.

Pathophysiology of Alcoholic liver disease

  • The cytochrome P450 enzymes (CYP) are a part of the microsomal ethanol oxidizing system. These are a large group of enzymes involved in numerous oxidizing reactions on different substrates. They catalyze many different reactions in order to make them in to more polar metabolites that are easier to excrete.[16]
  • Ethanol metabolism additionally promotes lipogenesis through the inhibition of peroxisome proliferator activated receptor α (PPAR-α) and AMP kinase, as well as the stimulation of sterol regulatory element binding protein 1, which is a membrane bound transcription factor. The sequence of all these events results in a fat storing metabolic remodeling of the liver.[33][34][35]
  • Two key factors that play an important role in the inflammatory process that leads to the alcohol mediated liver injury are:[36][37]
  • Endotoxin is associated to the lipopolysaccharide (LPS) component of the outer wall of gram-negative bacteria and is thought to be the key trigger in this inflammatory process.[38][39]
  • Gut permeability is the factor that is either enabling or preventing the transfer of the LPS-endotoxin from the intestinal lumen into the portal circulation.[40][41]
  • The fact that long term exposure to alcohol increases gut permeability has been observed in humans as LPS-endotoxin levels have been found to be elevated in patients with alcoholic liver injury.[42]
  • After the entry of LPS-endotoxin in to the portal circulation it binds to the LPS-binding protein, this is a key step in the inflammatory and histopathological response to alcohol ingestion.[43]
  • The LPS-LPS binding protein complex binds to the CD14 receptor on the cell surface membrane of the Kupffer cells in the liver.
  • Activation of these Kupffer cells requires 3 main cellular proteins:[44]
    • CD14 (monocyte differentiation antigen)[45]
    • Toll-like receptor 4 (TLR4)[46]
    • MD2, a protein, binds TLR4 with LPS-LPS binding protein
  • The TLR4 then signals activation of early growth response 1 (EGR1), which is an early gene-zinc-finger transcription factor.[47]
  • The nuclear factor-kB (NF-kB) and the TLR4 adapter also play an important role in the activation of the kupffer cells.[48]
  • EGR1 plays the pivotal role in lipopolysaccharide-stimulated TNF-α production.
  • In mice the absence of EGR1 prevents alcohol induced liver injury.[49]
  • Ethanol administration stimulates the release of mitochondrial cytochrome c and the expression of the Fas ligand, this leads to hepatic cell apoptosis mediated by the cascade-3 activation pathway.[50]
  • The cumulative effect of TNF-α and Fas-mediated apoptotic signals make the hepatocytes more susceptible to injury by stimulating an increase in natural killer T cells in the liver.[51]

Pathophysiology of Portal Hypertension

Increased resistance

Hyperdynamic circulation in portal hypertension

Genetics

  • Certain TERT (Telomerase reverese transcriptase)gene variants resulting in reduced telomerase activity has been found to be a risk factor for sporadic cirrhosis[66]
  • An uncharacterized nucleolar protein, NOL11, has a role in the pathogenesis of North American Indian childhood cirrhosis[67]
  • Loss of interaction between the C-terminus of Utp4/cirhin and other SSU processome proteins may cause North American Indian childhood cirrhosis[68]
  • Genes are involved in the pathogenesis of portal hypertension include the following:
Gene OMIM number Chromosome Function Gene expression in portal hypertension Notes
Deoxyguanosine kinase (DGUOK) 601465 2p13.1 DNA replication Point mutation Mutation leads to:[69]

Homozygous missense mutation leads to:[70]

Adenosine deaminase (ADA) 608958 20q13.12 Irreversible deamination of adenosine and deoxyadenosine in the purine catabolic pathway Reduced[71] Some roles in modulating tissue response to IL-13

The main effects of IL-13 are:[72]

Phospholipase A2 (PL2G10) 603603 16p13.12 Catalyzing the release of fatty acids from phospholipids Reduced[71] Identifier of PL2G10 expression:
Cytochrome P450, family 4, subfamily F, polypeptide 3 (CYP4F3) 601270 19p13.12 Catalyzing the omega-hydroxylation of leukotriene B4 (LTB4) Increased[71] -
Glutathione peroxidase 3 (GPX3) 138321 5q33.1 Reduction of glutathione which reduce:[73] Increased[71] Protects various organs against oxidative stress:[74]
Leukotriene B4 (LTB4) 601531 14q12 Include:[75] Mutated Increase blood flow to target tissue (esp. heart) about 4 times more.[76]
Prostaglandin E receptor 2 (PTGER2) 176804 14q22.1 Various biological activities in diverse tissues Reduced[71] -
Endothelin (EDN1) 131240 6p24.1 Vasoconstriction[77] Increased The most powerful vasoconstrictor known[78]
Endothelin receptor type A (EDNRA) 131243 4q31.22-q31.23 Vasoconstriction through binding to endothelin Reduced[71] Directly related to hypertension in patients[77]
Natriuretic peptide receptor 3 (NPR3) 108962 5p13.3 Maintenance of: Increased[71] Released from heart muscle in response to increase in wall tension. ANP can modulate blood pressure by binding to NPR3[79]
Cluster of differentiation 44 (CD44) 107269 11p13 Reduced[71]
Transforming growth factor (TGF)-β 190180 19q13.2 Reduced[71] Hyper-expressed in African-American hypertensive patients[84]
Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4) 607577 8p21.3 Increasing phosphatase activity in intracellular membrane-bound nucleosides Reduced[71] -
ATP-binding cassette, subfamily C, member 1 (ABCC1) 158343 16p13.11 Multi-drug resistance in small cell lung cancer[85] Reduced -

Associated Conditions

 
 
 
 
 
 
 
 
 
 
Portal Hypertension
associated conditions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunological disorders
 
Infections
 
Medication and toxins
 
Genetic disorders
 
Prothrombotic conditions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Common variable immunodeficiency syndrome[86]
Connective tissue diseases[87]
Crohn’s disease[88]
Solid organ transplant
•• Renal transplantation[89]
•• Liver transplantation[90]
Hashimoto's thyroiditis[91]
Autoimmune disease[92]
 
Bacterial intestinal infections
• Recurrent E.coli infection[93]
Human immunodeficiency virus (HIV) infection[94]
Antiretroviral therapy[95]
 
Thiopurine derivatives
•• Didanosine
•• Azathioprine[96]
•• Cis-thioguanine[97]
Arsenicals[98]
Vitamin A[99]
 
• Adams-Olivier syndrome[100]
Turner syndrome[101]
• Phosphomannose isomerase deficiency[102]
• Familial cases[103]
 
Inherited thrombophilias [104]
Myeloproliferative neoplasm[104]
Antiphospholipid syndrome[104]
Sickle cell disease[105]
 
 

Gross Pathology

Macroscopically, the liver may initially be enlarged, but with progression of the disease, it becomes smaller. Its surface is irregular, the consistency is firm, and the color is often yellow (if associates steatosis). Depending on the size of the nodules there are three macroscopic types: micronodular, macronodular and mixed cirrhosis.

  • In the micronodular form (Laennec's cirrhosis or portal cirrhosis) regenerating nodules are under 3 mm.
  • In macronodular cirrhosis (post-necrotic cirrhosis), the nodules are larger than 3 mm.
  • The mixed cirrhosis consists of a variety of nodules with different sizes.

Gross Pathology

Cirrhosis

On gross pathology there are two types of cirrhosis:

Micronodular cirrhosis - By Amadalvarez (Own work), via Wikimedia Commons[106]
Macronodular cirrhosis[107]

Splenomegaly

On gross pathology, diffuse enlargement and congestion of the spleen are characteristic findings of splenomegaly.

Splenomegaly - By Amadalvarez (Own work), via Wikimedia Commons[108]

Esophageal Varices

On gross pathology, prominent, congested, and tortoise veins in the lower parts of esophagus are characteristic findings of esophageal varices.

Esophageal varices[109]

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Microscopic Pathology

Microscopically, cirrhosis is characterized by regeneration nodules surrounded by fibrous septa. In these nodules, regenerating hepatocytes are disorderly disposed. Portal tracts, central veins and the radial pattern of hepatocytes are absent. Fibrous septa are important and may present inflammatory infiltrate (lymphocytes, macrophages). If it is a secondary biliary cirrhosis, biliary ducts are damaged, proliferated or distended - bile stasis. These dilated ducts contain inspissated bile which appears as bile casts or bile thrombi (brown-green, amorphous). Bile retention may be found also in the parenchyma, as the so called "bile lakes".[110]

Microscopic Pathology

Cirrhosis

Robbins definition of microscopic histopathological findings in cirrhosis includes (all three is needed for diagnosis):[111]

Cirrhosis with bridging fibrosis (yellow arrow) and nodule (black arrow) - By Nephron, via Librepathology.org[112]

Esophageal varices

The main microscopic histopathological findings in esophageal varices are:

Esophageal varices with submucosal vein (black arrow), via Librepathology.org[113]

Hepatic amyloidosis

The main microscopic histopathological findings in hepatic amyloidosis is amorphous extracellular pink stuff on H&E staining.

Hepatic amyloidosis with amorphous amyloids (black arrow) and normal hepatocytes (blue arrow), via Librepathology.org[114]

Congestive hepatopathy

The main microscopic histopathological findings in congestive hepatopathy (due to heart failure or Budd-Chiari syndrome) are:

Congestive hepatopathy with central vein (yellow arrowhead), inflammatory cells, Councilman body (green arrowhead), and hepatocyte with mitotic figure (red arrowhead), via Librepathology.org[115]

Chronic active hepatitis - Cirrhosis

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Micronodular cirrhosis

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Primary biliary cirrhosis

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